Tuesday, September 01, 2009

Human Y Chromosome Mutation Rates

One thing men are really good at is making mistakes—just ask any woman. When it comes to mutations we are ten times better than women at ensuring the evolution of the species.

Knowing the actual rate of mutation in humans—or any other species—is important for many reasons. For one thing, it tells us about the maximum possible rate of evolution. For another, it gives us an important clue about the differences between beneficial, detrimental, and neutral alleles.

It's a lot more difficult to measure mutation rates than you might imagine. In theory, you could sequence the genomes of hundreds of parents and their offspring and identify mutations that must have occurred in the germ lines of the parents. In practice, this is far too expensive and time-consuming and, besides, it will miss any severely detrimental mutations.

But let's say you did the experiment in spite of the time and money. If the measured mutation rate turned out to be close to the calculated value, then you could assume that most of the mutations were neutral. A few might be beneficial.

Another possibility is to measure the number of differences between two individuals who are separated by a large number of generations. In this case you are measuring the combined effect of mutation and the fixation of alleles in a population. This is what we do whenever we compare gene sequences from different species.

Alleles can be fixed by natural selection or by random genetic drift. If most are fixed by natural selection (adaptation) then you'll learn very little about the overall mutation rate aside from a minimum estimate. That's because you don't know the fitness of every allele and how fast it became fixed in the population and you don't know how many mutations were detrimental or neutral, and what happened to them.

Calculating the rate of evolution in terms of nucleotide substitutions seems to give a value so high that many of the mutations must be neutral ones.

Motoo Kimura (1968)However, you have a fighting chance if most mutations give rise to neutral alleles. In that case, the overall rate of fixation by random genetic drift is the same as the mutation rate [see: Random Genetic Drift and Population Size]. The data suggest that this is the correct scenario. When we compare individual genes from different species, the observed differences are consistent with the expected result if most of the differences are due to the fixation of neutral alleles by random genetic drift.

For the comparison between humans and chimpanzees, the estimated rates are remarkably consistent. They range from about 2 × 10-8 to about 5 × 10-8 mutations per nucleotide (base pair) per generation (Nachman, 2004; Britten, 2002). This agrees with the known error rate of DNA replication, which is about 10-10 per nucleotide per replication. Since there are about 400 DNA replications between the male zygote and mature sperm, this translates to 4 × 10-8 mutations per nucleotide per generation [see, Mutation Rates].

This is where men come in. There are many fewer cell divisions in the female line—about 30—so the egg contributes fewer mutations than the sperm. In fact, for most purposes we can ignore women in these calculations. Men have another big advantage. They have a Y chromosomes that's passed down directly from father to son and it doesn't recombine with any female chromosomes.1 You don't need to worry about fixation.

If you sequence Y chromosomes from related men you can get a direct estimate of the mutation rate provided most of the alleles are neutral. It's best to choose men who are distantly related since there won't be many differences between closely related men. Two sons, for example, are likely to have identical Y chromosomes.

Xue et al. (2009) did the experiment [Human mutation rate revealed]. They sequenced the Y chromosomes of two men who were separated by 13 generations. After eliminating repetitive regions, the relevant region of comparison was 10.15 × 106 nucleotides (base pairs, 10.15 Mb). The men differ at four confirmed sites. This gives a mutation rate of 3.0 × 10-8 per generation or 0.75 × 10-10 per nucleotide per DNA replication.

The agreement is remarkable. What this means is that we have a good handle on the mutation rate in humans and we have growing evidence that most mutations are neutral (i.e. most of our genome is junk).

1. This isn't strictly correct but you can ignore the small regions where recombination is possible.

I saw the paper a few days ago and earlier today I was thinking exactly about these issues.

It has occurred many time to me that the whole "debate" about evolution is so tragically far removed from the actual science, that we often focus more on fighting with lunatics than on reflecting on the implications of the science.

Because I highly doubt there are any people in the creationism/ID crowd that actually understand how much worse than what they are fighting against the neutral theory of molecular evolution really is (from their persepctive), and on how solid ground (both theoretically and in terms of support by the data) it is.

Of course, this only shows how ignorant they are, but it also shifts the focus away from the more productive discussions we could be having.

To add to what Bjørn said, the mutations might also appear neutral because they make a functional difference but it is too small to observe easily or to cause a significant selection pressure.

Suppose a human baby is born able to synthesise vitamin C. How would we know? Well, in theory it might go for a long time without eating any citrus fruits, and it wouldn't develop scurvy. OK, and how likely is that? Well, not likely. And would anyone report it? Probably not, they'd chalk it up to good luck.

More generally one could say that two alleles that code for different trait values may very well happen to result in equal fitness. Brown eyes vs. blue eyes in populations where there are plenty of both, for example.

Now somebody please correct me if I'm wrong, but doesn't the fact that there is redundancy in the third position of many codons mean that even functional dna sites (ie. those that are expressed and result in protein formation) can experience neutral mutations?

To Dave, yes... but this assumes there is no extreme codon bias in the organism in question. Strong codon bias may have an effect on translation of these "redundant" codons. Probably not an issue for mammalian Y chromosomes.

The meme, that most of our genome is junk, should have died in the 1970s. It appears that the human ability, to recirculate bad copies of an opinion, is quite resilient. Alternative splicing discoveries continue to leave the classic gene expression model behind. Go in peace and marginalize my introns no more.

BTW, not only is the claim that there is no junk DNA in human genome bogus, but a number of features of the human and other eukaryotic genomes are only explainable in the light of understanding the quantitative balance between selection and mutational processes (and how the latter can end up dominating the process under certain conditions which happen to be met in most eukaryotes).

Alternative splicing is a particularly bad example to use because while there might be advantage of having alternative isoforms of genes, this:

A) does not explain how introns arose initiallyB) does not explain why we have so many of them compared to the number of functional alternative splicing eventsC) does not explain why introns are so long in humans and so short in other speciesD) does not explain why there are no introns in prokaryotesE) does not explain a number of other peculiar features of the system in mammals and other eukaryotes

All of the above are only explainable by the neutral theory of molecular evolution

I think you should find out more about Kimura as a constructivist mathematician. The question of the moment is:

where is the constructivist intervention in Kimura's argument?

As you will see from the paper below, historians are now approaching this question with respect to Darwin.

They will certainly start approaching it with regard to Kimura.

You definitely owe it to yourself to read A. Garciadiego, BERTRAND RUSSELL AND THE ORIGINS OF THE SET-THEORETIC 'PARADOXES.'

Kimura's mathematical orientation--indeed his whole rhetorical orientation--comes from Malecot, who got his approach from Borel.

Borel, along with Russell and Poincare, was one of the now-discredited purveyors of the "paradoxes" and they renewed the constructivist insistence that argumentation avoid "paradox" by containing an arbitrary insertion in the logic.

Hence the quesion posed about Kimura.

You are very, very out of touch with what is going on in theoretical biology. Hurry up and put yourself in touch with it.

Laurence A. Moran

Larry Moran is a Professor Emeritus in the Department of Biochemistry at the University of Toronto. You can contact him by looking up his email address on the University of Toronto website.

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The Sandwalk is the path behind the home of Charles Darwin where he used to walk every day, thinking about science. You can see the path in the woods in the upper left-hand corner of this image.

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Quotations

The old argument of design in nature, as given by Paley, which formerly seemed to me to be so conclusive, fails, now that the law of natural selection has been discovered. We can no longer argue that, for instance, the beautiful hinge of a bivalve shell must have been made by an intelligent being, like the hinge of a door by man. There seems to be no more design in the variability of organic beings and in the action of natural selection, than in the course which the wind blows.Charles Darwin (c1880)Although I am fully convinced of the truth of the views given in this volume, I by no means expect to convince experienced naturalists whose minds are stocked with a multitude of facts all viewed, during a long course of years, from a point of view directly opposite to mine. It is so easy to hide our ignorance under such expressions as "plan of creation," "unity of design," etc., and to think that we give an explanation when we only restate a fact. Any one whose disposition leads him to attach more weight to unexplained difficulties than to the explanation of a certain number of facts will certainly reject the theory.

Charles Darwin (1859)Science reveals where religion conceals. Where religion purports to explain, it actually resorts to tautology. To assert that "God did it" is no more than an admission of ignorance dressed deceitfully as an explanation...

Quotations

The world is not inhabited exclusively by fools, and when a subject arouses intense interest, as this one has, something other than semantics is usually at stake.
Stephen Jay Gould (1982)
I have championed contingency, and will continue to do so, because its large realm and legitimate claims have been so poorly attended by evolutionary scientists who cannot discern the beat of this different drummer while their brains and ears remain tuned to only the sounds of general theory.
Stephen Jay Gould (2002) p.1339
The essence of Darwinism lies in its claim that natural selection creates the fit. Variation is ubiquitous and random in direction. It supplies raw material only. Natural selection directs the course of evolutionary change.
Stephen Jay Gould (1977)
Rudyard Kipling asked how the leopard got its spots, the rhino its wrinkled skin. He called his answers "just-so stories." When evolutionists try to explain form and behavior, they also tell just-so stories—and the agent is natural selection. Virtuosity in invention replaces testability as the criterion for acceptance.
Stephen Jay Gould (1980)
Since 'change of gene frequencies in populations' is the 'official' definition of evolution, randomness has transgressed Darwin's border and asserted itself as an agent of evolutionary change.
Stephen Jay Gould (1983) p.335
The first commandment for all versions of NOMA might be summarized by stating: "Thou shalt not mix the magisteria by claiming that God directly ordains important events in the history of nature by special interference knowable only through revelation and not accessible to science." In common parlance, we refer to such special interference as "miracle"—operationally defined as a unique and temporary suspension of natural law to reorder the facts of nature by divine fiat.
Stephen Jay Gould (1999) p.84

Quotations

My own view is that conclusions about the evolution of human behavior should be based on research at least as rigorous as that used in studying nonhuman animals. And if you read the animal behavior journals, you'll see that this requirement sets the bar pretty high, so that many assertions about evolutionary psychology sink without a trace.

Jerry Coyne
Why Evolution Is TrueI once made the remark that two things disappeared in 1990: one was communism, the other was biochemistry and that only one of them should be allowed to come back.

Sydney Brenner
TIBS Dec. 2000
It is naïve to think that if a species' environment changes the species must adapt or else become extinct.... Just as a changed environment need not set in motion selection for new adaptations, new adaptations may evolve in an unchanging environment if new mutations arise that are superior to any pre-existing variations

Douglas Futuyma
One of the most frightening things in the Western world, and in this country in particular, is the number of people who believe in things that are scientifically false. If someone tells me that the earth is less than 10,000 years old, in my opinion he should see a psychiatrist.

Francis Crick
There will be no difficulty in computers being adapted to biology. There will be luddites. But they will be buried.

Sydney Brenner
An atheist before Darwin could have said, following Hume: 'I have no explanation for complex biological design. All I know is that God isn't a good explanation, so we must wait and hope that somebody comes up with a better one.' I can't help feeling that such a position, though logically sound, would have left one feeling pretty unsatisfied, and that although atheism might have been logically tenable before Darwin, Darwin made it possible to be an intellectually fulfilled atheist

Richard Dawkins
Another curious aspect of the theory of evolution is that everybody thinks he understand it. I mean philosophers, social scientists, and so on. While in fact very few people understand it, actually as it stands, even as it stood when Darwin expressed it, and even less as we now may be able to understand it in biology.

Jacques Monod
The false view of evolution as a process of global optimizing has been applied literally by engineers who, taken in by a mistaken metaphor, have attempted to find globally optimal solutions to design problems by writing programs that model evolution by natural selection.